This project will examine the in vivo actions of a newly described putative dopaminotrophic (DA) factor, glial cell-derived neurotrophic factor (GDNF) in rats. The proposal will test the hypotheses that GDNF is a specific trophic factor for developing and mature midbrain DA neurons, that GDNF will support human as well as rat DA circuits, and that GDNF will counteract the deleterious effects of dopaminergic neurotoxins. It is proposed to examine actions of GDNF on dopaminergic pathways in situ in rats and mice. Interactions of GDNF with dopaminergic neurotoxins, such as 6-OHDA (rats) and MPTP (mice) will be evaluated both with "protection' and with facilitation of regeneration protocols. Target appropriateness will be evaluated in situ. GDNF will be studied in mature and immature syngeneic and allogeneic intracranial grafts and in immature human xenografts to aid further insight into the utility of this molecule to augment growth, differentiation, maintenance, and survival of DA neurons. This proposal will also examine GDNF effects on DA circuitry in aged non- lesioned rats, to test hypothesis about reversal of senescence-induced dopaminergic dysfunction. Finally, a second TGF-beta family molecule, OP-1 will be evaluated for dopaminotrophic activity int eh 6-OHDA lesion model. Actions of GDNF will be evaluated using behavioral, histochemical and in vivo electrochemical techniques. Neurochemical and electrophysiological protocols will also be utilized. Markers for apoptosis will be utilized to differentiate between survival-promoting and proliferative actions of GDNF on DA neurons. Project 3 will also provide lesioned/transplanted animals and behavioral/electrophysiological/histochemical evaluations for many of the other projects in this center.